This project will study the effects of both endogenous and exogenous insulin in patients with diabetes mellitus. Endogenous insulin will be quantitated by measurement of serum and urine C-peptide, and the pattern of action of exogenous insulin will be assessed, in the presence of circulating insulin-antibodies, by measurement of serum free and total insulin. New methods for measuring insulin-antibodies in the circulation will be developed. Using these laboratory techniques, we will study the relationships of endogenous and exogenous insulin to: (1) normalization of carbohydrate tolerance, (2) the clinical control of diabetes which can be achieved with insulin, (3) the development of diabetic complications. To accomplish this, diabetic patients will have endogenous insulin measured during standard glucose tolerance tests, and their pancreatic beta-cell reserve will be related to diabetic stability or instability, quantitatively defined on the basis of variability in blood and urine glucose. A separate prospective study of diabetic patients will relate endogenous insulin reserve to development of late complications of diabetes. Studies of ambulatory diabetic subjects living on the research ward will permit evaluation of the free-insulin response to exogenous insulin administration, and hopefully will lead to better means of deciding on insulin dosage schedules for individual patients. The role of exogenous insulin in diabetic control will be further defined by studies involving a newly developed glucose-controlled insulin infusion system, or artificial pancreas, in which insulin is infused on a continuous basis. By studying the free insulin levels needed to obtain normal glucose values, we can evaluate the roles of exogenous insulin and insulin antibodies in affecting glucose tolerance in the diabetic patient.